The compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine was first disclosed in the International patent application published as WO 03/029232. Later, International patent applications including WO 2007/144005, WO 2011/023194 and WO 2010/121621 have disclosed crystalline forms, manufacturing processes, formulations, and in particular liquid formulations of said compound. World Health Organization (WHO) has recommended the INN name “vortioxetine” for 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine. Vortioxetine obtained first regulatory approval in September 2013 in the United States of America for the treatment of major depressive disorder and has since then obtained approvals for similar indications throughout the World.
Vortioxetine has multimodal activity, and it has been shown to be an antagonist on the 5-HT3, 5-HT7 and 5-HT1D receptors, an agonist at the 5-HT1A receptor and a partial agonist at the 5-HT1B receptor, and an inhibitor of the serotonin transporter (SERT). 5-HT abbreviates 5-hydroxy tryptamine, i.e. serotonin. Moreover, vortioxetine has demonstrated to increase the levels of important neurotransmitters including serotonin, noradrenaline, dopamine, acetylcholine and histamine in specific areas of the brain [J. Med. Chem., 54, 3206-3221, 2011; Pharmacol. & Therap., 145, 43-57, 2015].
A significant drawback for treatment of depression using oral serotonin reuptake inhibitors is the lag-period between onset of treatment and onset of action which can be many weeks.
Several advantages have been suggested for intravenous (IV) administration of antidepressants compared to oral administration. IV administration avoids first-pass metabolism, and compliance is less of a problem compared to oral administration. In addition, it has been suggested that the IV setting itself may have a favourable impact on the treatment outcome. Finally, and with particular relevance in the present context, some reports in prior art suggest a faster onset of action for IV administration although only a few studies have applied the double-blind/double-dummy study design needed to properly compare onset of action between oral and IV administration of antidepressants.
Häberli in Pharma-Kritik, 10, 41-44, 1988 reviews studies comparing clomipramine (tricyclic antidepressant (TCA) with mainly serotonin reuptake inhibitory activity) and maprotilin (tetracyclic antidepressant with mainly noradrenaline reuptake inhibitory activity) in oral and IV administration settings. The conclusion is that antidepressant IV therapy has failed to deliver on the promise of faster onset of action.
Oral and IV administration of amitryptilin (TCA with serotonin and also noradrenaline reuptake inhibitory activity) have been compared in a double-blind/double-dummy study [J Clin Psychpharm 20, 417-422, 2000]. No difference in onset of action between the two treatments could be detected.
Oral and IV administration of citalopram (selective serotonin reuptake inhibitor (SSRI)) have been compared in several studies. Neuropsychiatrie 6, 65-71, 1992 reports on an open-label study where depressed patients received repeated oral (N=475) or IV citalopram (N=284) for 10-14 days followed by 4-6 weeks of oral treatment. An earlier onset of action in the IV treated group was observed although it also has to be noticed that the mean dose during the first 10-14 days for the IV treated patients was twice that of the dose for the orally treated patients. More than 50% of the participating doctors with patients on initial IV treatment indicated that an expectation of faster onset was the main reason for administering IV treatment to their patients.
C̆esko-Slovenská Psychiatrie, 6, 331-339, 1993 reports on a study where 101 depressed patients were enrolled in an open-label study to receive either 28 days oral citalopram or 14 days IV citalopram followed by 14 days oral citalopram. A significantly faster onset of action was observed in the IV treated group.
J Affec Dis, 49, 203-210, 1998 reports on a double-blind, double-dummy study comparing oral and IV administration of citalopram. 60 depressed patients were treated with either repeated citalopram tablets and placebo IV or repeated citalopram IV and placebo tablets for 10 days followed by oral citalopram for additional 32 days. No statistical difference in onset of action could be detected between the two groups for any efficacy parameter although a tendency toward a quicker onset of action was seen when measured as percentage of patients with more than 50% reduction of the score on the Hamilton Depression Scale compared to baseline.
J Affect Dis 58, 201-209, 2000 reports on a further double-blind, double-dummy study comparing oral and IV administration of citalopram. Depressed patients were randomised to repeated citalopram tablets and placebo IV (N=119) or repeated citalopram IV and placebo tablets (N=135) for 8 days followed by 34 days of oral citalopram treatment. No difference in the Montgomery-Åsberg Depression Rating Scale (MADRS) at day 8 was found, which was the primary efficacy end-point. However, improvements on the Global Clinical Impression scale at day 8 were observed for more patients in the IV arm than in the oral arm.
In conclusion, past well-controlled studies have generally failed to show a faster onset of action for antidepressants, and in particular for antidepressant with serotonin reuptake inhibitory effect, administered via the IV route compared to oral administration.
Basic & Clin Pharmacol & Tox, 111, 198-205, 2012 discloses a series of studies to define the clinical pharmacokinetics of vortioxetine. One of the studies was a single-dose, open-label, 2-way crossover study where healthy volunteers received oral and IV vortioxetine with a wash-out period of at least 18 days between the two administrations.
One aim of the present invention is to provide a treatment regime for vortioxetine which achieves a faster onset of action compared to orally administered vortioxetine.